Interplay between PKCδ and Sp1 on Histone Deacetylase Inhibitor-Mediated Epstein-Barr Virus Reactivation

Tsai, Ping-Huei; Lin, Sheng‐Hsuan; Weng, Pei Lun; Tsai, Shu Chun; Lin, Jiun Han; Chou, Ya-Ching; Tsai, Ching Hwa

doi:10.1128/jvi.01602-10

Cited by 37 publications

(48 citation statements)

References 61 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To determine further whether IL-32 affects PKC␦-mediated Zp activation, we coexpressed IL-32 and enhanced GFP (EGFP)-derived wild-type PKC␦ (WT-PKC␦) or a kinase-inactive form of PKC␦ (DN-PKC␦) and determined the Zp activity. The results were similar to those in our previous work: overexpression of WT-PKC␦, but not DN-PKC␦, induced Zp activity (38). Of note, IL-32 expression decreased WT-PKC␦-mediated Zp activation (Fig.…”

Section: Expression Pattern and Cellular Distribution Of Il-32 Insupporting

confidence: 81%

“…In this work, we uncovered a novel mechanism of a cellular factor which modulates the EBV life cycle. Our previous studies indicated that PKC␦ is an important modulator of EBV lytic cycle progression and that overexpression of PKC␦ significantly stimulates Zp activity (38,54). In this study, we clearly showed that IL-32 downregulates Zp activation by interacting with PKC␦ and inhibiting the nuclear translocation of PKC␦ to maintain viral latency.…”

Section: Discussionmentioning

confidence: 49%

“…The IL-32␤-Flag plasmids were constructed by insertion of a full-length IL-32␤ fragment into pCMV-tag-2B vector at the 5= EcoRI site and 3= XhoI site. The plasmids of pEGFP-N1-derived wild-type PKC (WT-PKC␦), the kinase-inactive form of PKC␦ (DN-PKC␦), Zta promoter (Zp), and ZID deletion of Zp (⌬ZID-Zp) were described in our previous study (38).…”

Section: Methodsmentioning

confidence: 99%

“…Previous studies have shown that Sp1, Sp3, and MEF2D can potentially bind to the ZID element (51)(52)(53). Furthermore, our previous report showed that the ZID region of Zp is essential for PKC␦-mediated Zp transactivation via Sp1 (38). To investigate further whether IL-32 repressed Zp activation through the PKC␦-responsible ZID domain, a reporter assay was performed with ZID deletion of Zp (⌬ZID-Zp).…”

Section: Expression Pattern and Cellular Distribution Of Il-32 Inmentioning

confidence: 99%

See 3 more Smart Citations

Maintenance of Epstein-Barr Virus Latent Status by a Novel Mechanism, Latent Membrane Protein 1-Induced Interleukin-32, via the Protein Kinase Cδ Pathway

Lai

Chou

Lin

et al. 2015

J Virol

Self Cite

View full text Add to dashboard Cite

Epstein-Barr virus (EBV), an oncogenic herpesvirus, has the potential to immortalize primary B cells into lymphoblastoid cell lines (LCLs) in vitro.During immortalization, several EBV products induce cytokines or chemokines, and most of these are required for the proliferation of LCLs. Interleukin-32 (IL-32), a recently discovered proinflammatory cytokine, is upregulated after EBV infection, and this upregulation is detectable in all LCLs tested. EBV latent membrane protein 1 (LMP1) is responsible for inducing IL-32 expression at the mRNA and protein levels. Mechanistically, we showed that this LMP1 induction is provided by the p65 subunit of NF-B, which binds to and activates the IL-32 promoter. Furthermore, the short hairpin RNA (shRNA)-mediated depletion of endogenous LMP1 and p65 in LCLs suppressed IL-32 expression, further suggesting that LMP1 is the key factor that stimulates IL-32 in LCLs via the NF-B p65 pathway. Functionally, knockdown of IL-32 in LCLs elicits viral reactivation and affects cytokine expression, but it has no impact on cell proliferation and apoptosis. Of note, we reveal the mechanism whereby IL-32 is involved in the maintenance of EBV viral latency by inactivation of Zta promoter activity. This atypical cytoplasmic IL-32 hijacks the Zta activator protein kinase C␦ (PKC␦) and inhibits its translocation from the cytoplasm to the nucleus, where PKC␦ binds to the Zta promoter and activates lytic cycle progression. These novel findings reveal that IL-32 is involved in the maintenance of EBV latency in LCLs. This finding may provide new information to explain how EBV maintains latency, in addition to viral chromatin structure and epigenetic modification. IMPORTANCEEBV persists in two states, latency and lytic replication, which is a unique characteristic of human infections. So far, little is known about how herpesviruses maintain latency in particular tissues or cell types. EBV is an excellent model to study this question because more than 90% of people are latently infected. EBV can immortalize primary B cells into lymphoblastoid cell lines in vitro. Expression of IL-32, a novel atypical cytoplasmic proinflammatory cytokine, increased after infection. The expression of IL-32 was controlled by LMP1. In investigating the regulatory mechanism, we demonstrated that the p65 subunit of NF-B is required for this upregulation. Of note, the important biological activity of IL-32 was to trap protein kinase C␦ in the cytoplasm and prevent it from binding to the Zta promoter, which is the key event for EBV reaction. So, the expression of LMP1-induced IL-32 plays a role in the maintenance of EBV latency. E pstein-Barr virus (EBV) is a ubiquitous human gammaherpesvirus: more than 90% of the human population are latently infected (1). Of note, EBV has been reported to be associated with Burkitt's lymphoma (BL), Hodgkin's lymphoma (HL), natural killer (NK)/T-cell lymphoma, AIDS-associated lymphoma, and posttransplantation lymphoproliferative disorder (PTLD) (2). The strongest evidence for EBV onco...

show abstract

Section: Expression Pattern and Cellular Distribution Of Il-32 Insupporting

confidence: 81%

Section: Discussionmentioning

confidence: 49%

Section: Methodsmentioning

confidence: 99%

Section: Expression Pattern and Cellular Distribution Of Il-32 Inmentioning

confidence: 99%

See 2 more Smart Citations

Maintenance of Epstein-Barr Virus Latent Status by a Novel Mechanism, Latent Membrane Protein 1-Induced Interleukin-32, via the Protein Kinase Cδ Pathway

Lai

Chou

Lin

et al. 2015

J Virol

Self Cite

View full text Add to dashboard Cite

show abstract

“…In order to analyze the growth of PRRSV, the viral supernatants from cell cultures were collected at the indicated time points after virus inoculation, and the determination of viral 50% tissue culture infective doses (TCID 50 ) was performed by the Reed-Muench method.…”

Section: Methodsmentioning

confidence: 99%

MicroRNA 373 Facilitates the Replication of Porcine Reproductive and Respiratory Syndrome Virus by Its Negative Regulation of Type I Interferon Induction

Chen

Shi

Zhang

et al. 2017

J Virol

View full text Add to dashboard Cite

MicroRNAs (miRNAs) play an important role in the regulation of immune responses. Previous studies have indicated that dysregulating the miRNAs leads to the immunosuppression of porcine reproductive and respiratory syndrome virus (PRRSV). However, it is not clear how PRRSV regulates the expression of host miRNA, which may lead to immune escape or promote the replication of the virus. The present work suggests that PRRSV upregulated the expression of miR-373 through elevating the expression of specificity protein 1 (Sp1) in MARC-145 cells. Furthermore, this work demonstrated that miR-373 promoted the replication of PRRSV, since miR-373 was a novel negative miRNA for the production of beta interferon (IFN-␤) by targeting nuclear factor IA (NFIA), NFIB, interleukin-1 receptor-associated kinase 1 (IRAK1), IRAK4, and interferon regulatory factor 1 (IRF1). We also found that both NFIA and NFIB were novel proteins for inducing the production of IFN-␤, and both of them could inhibit the replication of PRRSV. In conclusion, PRRSV upregulated the expression of miR-373 by elevating the expression of Sp1 and hijacked the host miR-373 to promote the replication of PRRSV by negatively regulating the production of IFN-␤.IMPORTANCE PRRSV causes one of the most economically devastating diseases of swine, and there is no effective method for controlling PRRSV. It is not clear how PRRSV inhibits the host's immune response and induces persistent infection. Previous studies have shown that PRRSV inhibited the production of type I IFN, and the treatment of type I IFN could efficiently inhibit the replication of PRRSV, so it will be helpful to design new methods of controlling PRRSV by understanding the molecular mechanism by which PRRSV modulated the production of IFN. The current work shows that miR-373, upregulated by PRRSV, promotes PRRSV replication, since miR-373 impaired the production of IFN-␤ by targeting NFIA, NFIB, IRAK1, IRAK4, and IRF1, and both NFIA and NFIB were antiviral proteins to PRRSV. In conclusion, this paper revealed a novel mechanism of PRRSV that impaired the production of type I IFN by upregulating miR-373 expression in MARC-145 cells.

show abstract

Inhibition of class I histone deacetylases by romidepsin potently induces Epstein-Barr virus lytic cycle and mediates enhanced cell death with ganciclovir

et al. 2015

View full text Add to dashboard Cite

Pan-histone deacetylase (HDAC) inhibitors, which inhibit 11 HDAC isoforms, are widely used to induce Epstein-Barr virus (EBV) lytic cycle in EBV-associated cancers in vitro and in clinical trials. Here, we hypothesized that inhibition of one or several specific HDAC isoforms by selective HDAC inhibitors could potently induce EBV lytic cycle in EBV-associated malignancies such as nasopharyngeal carcinoma (NPC) and gastric carcinoma (GC). We found that inhibition of class I HDACs, particularly HDAC-1, -2 and -3, was sufficient to induce EBV lytic cycle in NPC and GC cells in vitro and in vivo. Among a panel of selective HDAC inhibitors, the FDA-approved HDAC inhibitor romidepsin was found to be the most potent lytic inducer, which could activate EBV lytic cycle at~0.5 to 5 nM (versus~800 nM achievable concentration in patients' plasma) in more than 75% of cells. Upregulation of p21 WAF1 , which is negatively regulated by class I HDACs, was observed before the induction of EBV lytic cycle.The upregulation of p21 WAF1 and induction of lytic cycle were abrogated by a specific inhibitor of PKC-d but not the inhibitors of PI3K, MEK, p38 MAPK, JNK or ATM pathways. Interestingly, inhibition of HDAC-1, 22 and 23 by romidepsin or shRNA knockdown could confer susceptibility of EBV-positive epithelial cells to the treatment with ganciclovir (GCV). In conclusion, we demonstrated that inhibition of class I HDACs by romidepsin could potently induce EBV lytic cycle and mediate enhanced cell death with GCV, suggesting potential application of romidepsin for the treatment of EBV-associated cancers.

show abstract

Interplay between PKCδ and Sp1 on Histone Deacetylase Inhibitor-Mediated Epstein-Barr Virus Reactivation

Cited by 37 publications

References 61 publications

Maintenance of Epstein-Barr Virus Latent Status by a Novel Mechanism, Latent Membrane Protein 1-Induced Interleukin-32, via the Protein Kinase Cδ Pathway

Maintenance of Epstein-Barr Virus Latent Status by a Novel Mechanism, Latent Membrane Protein 1-Induced Interleukin-32, via the Protein Kinase Cδ Pathway

MicroRNA 373 Facilitates the Replication of Porcine Reproductive and Respiratory Syndrome Virus by Its Negative Regulation of Type I Interferon Induction

Inhibition of class I histone deacetylases by romidepsin potently induces Epstein-Barr virus lytic cycle and mediates enhanced cell death with ganciclovir

Contact Info

Product

Resources

About